Phase II study of weekly paclitaxel plus 24-h continuous infusion 5-fluorouracil,folinic acid and 3-weekly cisplatin for the treatment of patients with advanced gastric cancer

The aim of this study was to evaluate the toxicity and efficacy of combination chemotherapy with weekly 24-h continuous infusion of 5-fluorouracil (5-FU)/folinic acid, weekly paclitaxel and 3-weekly cisplatin in patients with unresectable, locally advanced or metastatic gastric adenocarcinoma. Between November 1999 and November 2001, 29 chemotherapy-naive patients (13 male and 16 female) with a median age of 56 years (range 22-72) were consecutively enrolled at three centers. 5-FU 2 g/m2 was given weekly over 24 h i.v. preceded by folinic acid 500 mg/m2 as a 2-h infusion. Paclitaxel 80 mg/m2 was administered as a 1-h infusion weekly and cisplatin 50 mg/m2 as 1-h infusion on days 8 and 29. Six weeks of therapy (days 1, 8, 15, 22, 29 and 36) followed by 1 week of rest was considered one cycle. A median of 3 cycles (range 1-5) was administered to 29 patients with a total of 73 cycles applied. All patients were assessable for toxicity and survival, 28 patients were assessable for response (one patient received less than one complete cycle and could not be evaluated for response). Four patients (14%) obtained a complete response and 10 patients (34%) a partial response (overall response rate 48%, 95% CI 29-68%). Seven patients (24%) had stable disease. Seven patients (24%) had progressive disease during or within 4 weeks after treatment. The median progression-free and overall survival times were 8 months (range 1-23) and 11 months (range 1-23), respectively. Overall toxicity was acceptable. Hematological toxicity was favorable with only one patient (3%) experiencing WHO grade 3/4 leukocytopenia and one patient (3%) WHO grade 3/4 anemia. Non-hematologic WHO grade 3/4 toxicities included alopecia in 19 (66%), nausea/vomiting in six (21%), diarrhea in six (21%), neurotoxicity grade 3 in three (10%) and infection in three (10%) patients. A total of 42 applications (10%) (range 0-5) had to be postponed and dose reductions of at least one drug was necessary in 37% of applications. In three patients (10%) treatment was stopped because of toxicity. All patients were treated on an outpatient basis. Thus, the combination of weekly paclitaxel, cisplatin and continuously infused 5-FU/folinic acid appears to be a highly active regimen for the treatment of patients with advanced gastric cancer. Compared with our previous experience with the same combination of drugs but using paclitaxel at 175 mg/m2 given every 3 weeks, the protocol with weekly application of paclitaxel 80 mg/m2 shows a reduced incidence of hematologic toxicity, particularly leukopenia. Other organ toxicities apart from a slightly higher incidence of peripheral neuropathy were comparable between the two treatment protocols. Efficacy with a response rate of 50% was well preserved by this weekly regimen.     

Prospective multicenter phase II study of irinotecan as third-line therapy in metastatic colorectal cancer and progression after bolus and infusional 5-fluorouracil

Irinotecan has proven anti-tumor activity as induction treatment in combination with 5-fluorouracil (5-FU) or as second-line treatment after 5-FU in patients with metastatic colorectal cancer. The aim of the present phase II study was to evaluate irinotecan as third-line chemotherapy in patients with colorectal cancer after sequential treatment with bolus 5-FU followed by an infusional 5-FU regimen. Patients pretreated with bolus 5-FU/folinic acid and the infusional 5-FU/folinic acid regimen were treated with 350 mg/m irinotecan i.v. once every 3 weeks in a multicenter phase II study. Tumor size was measured every cycle and treatment with irinotecan was continued until the occurrence of progressive disease or unacceptable toxicity. A total of 50 pretreated patients were included. Of the 45 evaluable patients, 13.3% [n=6, 95% confidence interval (CI) 5.1-26.8] attained a response (complete/partial response) to treatment lasting 5.6 months (95% CI 4.2-6.3) and in four patients response has been confirmed (8.9%, 95% CI 2.5-21.2). Disease stabilization was noted in 51.1% of the patients (n=23, 95% CI 35.8-66.3). The median duration of response/disease stabilization was 4.2 months (95% CI 3.2-6.0). Median overall survival was 7.9 months (95% CI 6.1-11.1), corresponding to a calculated 1-year survival of 28.3% (95% CI 15.2-41.3). Severe neutropenia occurred in 14% (n=7) and anemia grade III in 6% of the patients (n=3). The most frequent non-hematological toxicity grade III/IV related to treatment was diarrhea in 24% of the patients (n=12), followed by vomiting in 8% (n=4) and constipation as well as infection in two patients each (4%) (evaluable n=50). We conclude single-agent irinotecan is an effective and well-tolerable treatment in pretreated patients with metastatic colorectal cancer after failure of bolus and infusional 5-FU/folinic acid regimens. Elderly patients had the same probability to respond.     

Mitomycin C continuous infusion as salvage chemotherapy in pretreated patients with advanced gastric cancer

Our purpose was to evaluate the safety and therapeutic activity of continuously infused mitomycin C in patients with recurring or progressive metastatic gastric cancer following first-line chemotherapy. Patients were treated with mitomycin C 20 mg/m2 i.v. over a time period of 120 h followed by a 3-week rest period. All patients received prednisone 50 mg p.o. prophylactically for 5 days to prevent hemolytic uremic syndrome and pulmonary side effects. Twenty-two consecutively enrolled patients were assessable for toxicity and 20 for response evaluation completing at least one full course of chemotherapy (two patients evaluable but not measurable). Patient characteristics: median age: 63 years (39-76); Sex (M/ F): 13/9; median Karnofsky status: 70% (50-100%); resection of primary tumor n = 12 (55%); sites of metastases: liver n = 17 (77%), locally advanced n = 10 (45%), peritoneum n = 13 (59%), lungs n=5 (23%), bone n=3 (14%) and lymph nodes n=14 (64%). Previous chemotherapy regimens: bolus 5-FU/folinic acid n=6 (27%), ELF n=4 (18%), EAP n=3 (14%) and continuous 5-FU/folinic acid/cisplatin/paclitaxel n=9 (41%). In 20 evaluable patients one complete and five partial remissions were observed; overall response rate 30.0% [95% confidence interval (CI): 9.1-50.9%] with a median response duration of 2.1 months (range: 2-6). The median survival was 3.6 months (95% CI: 2.1-6.0) resulting in a 6-month survival rate of 30% since start of mitomycin C. WHO grade III/IV mucositis, diarrhea and fever/infection occurred in 9% of patients each. Cumulative thrombo- and leukocytopenia (WHO grade II/IV) were observed in four and two patients, respectively. Treatment had to be stopped early in two patients. No severe renal dysfunction, pulmonary toxicity or evidence of hemolytic uremic syndrome was observed. Fatigue during the 120 h infusion of mitomycin C was common (11 of 22 patients). We conclude that continuous infusion of mitomycin C is feasible on an outpatient basis, revealing an acceptable toxicity. Mitomycin C demonstrates single-agent activity in pretreated gastric cancer, but has only limited efficacy following cisplatin/paclitaxel-based first-line chemotherapy.     

Phase II trial of oxaliplatin combined with leucovorin and fluorouracil for recurrent/metastatic biliary tract carcinoma

Biliary tract carcinoma is often diagnosed at an advanced stage, and there is currently no established palliative standard of care. This phase II study investigated the efficacy and safety of combination chemotherapy of oxaliplatin, leucovorin, and 5-fluorouracil (5-FU) in biliary tract carcinoma. Patients with unresectable or recurrent biliary tract carcinoma were enrolled, including pretreated and chemotherapy-naive patients. Treatment consisted of intravenous oxaliplatin (100 mg/m2, day 1) followed by leucovorin (100 mg/m2, day 1) and 5-FU (1000 mg/m2, days 1 and 2). Treatment was repeated every 3 weeks. The efficacy and safety of the treatment were determined. Twenty-eight patients were evaluable, and a total of 166 cycles were administered (median five cycles). One complete response (3.6%) and five partial responses (17.9%) were noted, with a response rate of 21.5% [95% confidence interval (CI): 6.2-36.7], according to Response Evaluation Criteria in Solid Tumors criteria. The median time to progression and overall survival was 3.5 months (95% CI: 2.7-4.3) and 10.0 months (95% CI: 7.2-12.8), respectively. The 1-year survival rate was 17.8%. Grade 3/4 neutropenia and thrombocytopenia were recorded in 18 and 4% of the patients, respectively. No treatment-related death was observed. Oxaliplatin in combination with leucovorin and 5-FU should be considered a feasible chemotherapy regimen for patients with recurrent/metastatic biliary tract carcinoma.     

Phase II trial of 5-fluorouracil, folinic acid and recombinant alpha-2a-interferon in patients with advanced colorectal cancer

A clinical trial regimen modulating 5-fluorouracil (5-FU) with both folinic acid (FA) and recombinant alpha-2a-interferon (ralpha-2a-IFN) was noted to have a response rate of 54% and median survival of 16.3 months (Grem et al., J Clin Oncol 1993, 11: 1737-45). Reported herein is a phase II trial performed to further examine this regimen in metastatic colorectal cancer. Fifty-one patients with histologically proven, measurable advanced colorectal cancer with no prior therapy for metastatic disease were enrolled. ralpha-2a-IFN, 5 MIU/m2/day was given s.c. on days 1-7. FA, 500 mg/m2/day, and 5-FU, 370 mg/m2/day, were given i.v. on days 2-6. Cycles were repeated at 3 week intervals. Three complete and 12 partial responses were observed for an overall response rate of 29% (95% confidence interval: 18-45%). The median time to treatment failure and median survival were 4.6 and 15.5 months, respectively. Dose-limiting toxicities encountered were gastrointestinal, and included diarrhea, stomatitis, nausea and vomiting. These results do not support the concept of using concurrent ralpha-2a-IFN and FA as biochemical modulators of 5-FU. We observed increased toxicity and similar efficacy compared to using either modulator separately with 5-FU.     

Paclitaxel and cetuximab combination efficiency after the failure of a platinum-based chemotherapy in recurrent/metastatic head and neck squamous cell carcinoma

The addition of cetuximab (CTX) to the combination of cisplatin and 5-fluorouracil increases the overall survival (OS) in recurrent/metastatic head and neck squamous cell carcinoma. Only a few patients are eligible for this treatment because of its toxicity. The combination of CTX and paclitaxel (TXL) could be included in sequential treatment strategies. Patients were treated with CTX (400/250 mg/m) and TXL (60-80 mg/m) weekly until disease progression or unacceptable toxicity. Efficacy and safety outcomes were determined retrospectively. A total of 42 patients were included in this analysis. The overall response rate was 38% [95% confidence interval (CI); 23-53%]. The disease control rate with TXL and CTX combination was 74%. Seven (17%) patients progressed before the first evaluation. The median progression-free survival was 3.9 months [95% CI; 3.1-4.7 months] and the median OS was 7.6 months [95% CI; 5.3-9.9 months]. Neurotoxicity and skin rash were the most frequent grade≥2 toxicities, reported in 17 and 12% of patients, respectively. Previous chemotherapy seems to be associated with a lower response rate and progression-free survival but not with the OS. The combination of CTX and TXL was an active and well-tolerated treatment in this series of patients with a poor prognosis and who were mostly symptomatic.     

Weekly epirubicin and paclitaxel with granulocyte colony-stimulating factor support in previously untreated metastatic breast cancer patients: a phase II study

We conducted a phase II study to determine the activity and tolerability of weekly epirubicin-paclitaxel and granulocyte colony-stimulating factor in breast cancer patients untreated for metastatic disease. The phase II study was designed following the Simon optimal-two stage method. Patients received epirubicin 25 mg/m and paclitaxel 80 mg/m every week, and granulocyte colony-stimulating factor on days 2 and 4 for 24 consecutive weeks in the absence of progression. From 1999 to 2004, 53 patients entered the study; 1093 weekly courses were delivered, with a median number of cycles of 22. Patients received a median relative dose intensity of 94%. No hematological grade 3-4 toxicities were observed. One patient had one episode of grade 3 mucositis and two patients (3.8%) suffered grade 2 asthenia. Eight patients (15.1%) experienced grade 2 neutropenia, grade 2 anemia was registered in seven patients (13.2%). No cardiotoxicity was observed. Ten out of 53 patients (18.9, 95% confidence interval 8.3, 29.4%) showed a complete response, whereas 28 (52.8, 95% confidence interval 39.4, 66.3%) had a partial response, with an overall response rate of 71.7% (95% confidence interval 59.6, 83.8%). In addition, 14 patients (26.4%) had stable disease. Median time to progression was 12 months (95% confidence interval 7, 17). Median response duration was 14 months (range 3-60). The 1-, 3- and 5-year survival rates were 90.1, 68.0 and 56.6%, respectively. In untreated metastatic breast cancer patients, the weekly administration of epirubicin and paclitaxel with granulocyte colony-stimulating factor support seems to be extremely tolerable and active, and deserves further investigation into a phase III trial.     

三维适形放疗同步化疗治疗晚期直肠癌的临床观察

目的 观察三维适形放疗同步FOLFOX方案化疗治疗晚期直肠癌的临床疗效和毒副反应。方法 经病理证实的晚期直肠癌（包括局部晚期和远处转移）患者16例,行盆腔三野等中心放疗50Gy。常规分割剂量（2Gy,5次,周）,5周内完成,后针对直肠局部肿块行三维适形放疗加量至60Gy-64Gy。放疗前3d开始化疗．化疗方案为静脉滴注奥沙利铂（恒瑞生产,商品名：草酸铂）60rag／m2dl,亚叶酸钙200mg／m^2d1、2,氟尿嘧啶1600mg/min^2静脉持续给药46h,2周1次,2次为1周,共完成92周（184次）。结果 其中有15例按计划完成治疗。1例因未完成治疗周期而不计数在内,疗效评价CR2例（13.3%）,PR11例（73．3%）,NC2例（13．3%）,总有效率为86．7％。14例（93.3％）一般状况改善,12例（80％）生活质量明显提高。主要不良反应为骨髓抑制、消化道反应和末稍神经病变,经相应处理后恢复,无治疗相关死亡。结论 三维适形放疗同步FOLFOX方案化疗治疗晚期直肠癌安全、有效．毒副反应轻,可作为晚期直肠癌新的治疗方案。     

紫杉醇联合顺铂治疗晚期食管鳞癌临床观察

目的 观察紫杉醇联合顺铂治疗晚期食管鳞癌的疗效及不良反应.方法 用紫杉醇注射液175mg/m2静脉滴注3h,第1天;顺铂25mg/m2,静脉滴注,第1-3天.该方案治疗25例晚期食管鳞癌,3周为1个周期.结果 25例患者共完成化疗周期数为104个,其中完全缓解1例(4.1％),部分缓解10例(41.7％),稳定9例(37.5％),进展4例(16.7％),总有效率为45.8％(11/24).至末次随访,死亡20例,全组中位生存期11.0个月(95％CI:8.35～13.65个月),1年生存率37.3％.12例治疗有效病例的中位生存期为12.5个月(95％CI:9.11～ 15.90个月),治疗无效病例的中位生存期为8.0个月(95％CI:5.50～9.50个月),获治疗有效病例的中位生存期显著好于无效病例(P =0.022).主要毒副反应有:白细胞减少(Ⅲ度7例,Ⅳ度1例)、中性粒细胞减少(Ⅲ度5例,Ⅳ度1例)、血小板下降(Ⅲ度1例)和脱发(Ⅱ度19例).结论 紫杉醇联合顺铂方案治疗晚期食管癌有效安全,可作为晚期食管鳞癌首选化疗方案.     

Pegylated liposomal doxorubicin hydrochloride (PLD) and paclitaxel in recurrent or metastatic head and neck carcinoma: a phase I/II study conducted by the Hellenic Cooperative Oncology Group (HeCOG)

A phase I pharmacokinetics and dose-finding study and a phase II study of the combination of pegylated liposomal doxorubicin HCl (PLD) and paclitaxel were conducted in patients with recurrent or metastatic head and neck cancer (HNC). Sixty patients with recurrent or metastatic disease were enrolled in the study: 11 patients in the phase I study and 49 patients in the phase II study. In the phase I study, the initial dose level of PLD was 35 mg/m as a 1-h infusion with escalating increments of 5 mg/m until the maximum tolerated dose (MTD) was reached. A fixed dose of paclitaxel (175 mg/m) was administered as a 3-h infusion. The combination was administered every 28 days. Pharmacokinetic studies performed on 10 patients indicated that the sequence of drug administration did not cause clinically significant modifications in the pharmacokinetics of either drug. The MTD for PLD was 45 mg/m (dose level 3) and the dose-limiting toxicity was febrile neutropenia, occurring in three of five patients. The phase II dose of PLD was 40 mg/m (dose level 2) and a total of 214 cycles were delivered. Grade 3 or 4 neutropenia was observed in 26% patients and febrile neutropenia occurred in 16% of patients. Grade 3 palmar-plantar erythrodysesthesia (PPE) was recorded in only one patient. The overall response rate was 28% for patients with non-nasopharyngeal tumors [95% confidence interval (CI) 15-45%] and 28.6% for the study population (95% CI 17-43%). The median survival for the study population was 9.7 months; 1-year survival was 38%. We conclude that the recommended dose for the combination of PLD and paclitaxel is 40 and 175 mg/m every 28 days, without granulocyte colony stimulating factor support. The combination of paclitaxel with PLD demonstrated activity in recurrent or metastatic HNC, a favorable toxicity profile and relative ease of administration.     

Paclitaxel versus docetaxel for advanced gastric cancer: a randomized phase II trial in combination with infusional 5-fluorouracil

Taxanes have clearly demonstrated activities against gastric cancer. We compared the combination of paclitaxel plus 5-fluorouracil (5-FU) (PF) with docetaxel plus 5-FU (DF) as first-line chemotherapy in patients with measurable metastatic gastric cancer. Seventy-seven patients were randomly assigned to receive paclitaxel 175 mg/m2 or docetaxel 75 mg/m2 on day 1, in combination with 5-FU 500 mg/m2 continuous infusion on days 1-5. Treatment was repeated every 3 weeks. Of 314 chemotherapy cycles delivered (median 5 in both groups), dose reduction was required more frequently in the DF group, being 9 and 19%, respectively (P<0.01). PF was associated with, although statistically insignificant, substantially less grade 3 or 4 toxicities than DF (68 versus 85%; P=0.09). Global quality of life was similar in both groups, but substantive differences in many symptom scores including pain, dyspnea, constipation and diarrhea favored PF. There were no significant differences in therapeutic efficacy between PF and DF with respect to response rate (42 versus 33%, respectively; P=0.53), and failure-free (3.6 versus 4.2 months; P=0.92) and overall survival (9.9 versus 9.3 months; P=0.42). Both PF and DF appear to have efficacy against metastatic gastric cancer, with different, but acceptable, safety profiles.     

Biweekly docetaxel and vinorelbine with granulocyte colony-stimulating factor support for patients with anthracycline-resistant metastatic breast cancer

This phase II trial evaluated the efficacy and toxicity of vinorelbine 25 mg/m2 plus docetaxel 60 mg2/m administered on day 1, every 2 weeks with granulocyte colony-stimulating factor support (G-CSF, 5 microg/kg/day, days 3-7) as primary prophylaxis in patients with histologically confirmed metastatic breast cancer (MBC) and previously treated with anthracyclines in the adjuvant or in the first-line setting. A total of 48 patients received 352 cycles (median 8, range 2-10). All patients were included in the efficacy and safety evaluation on an intent-to-treat analysis. Eight patients (17%) showed a complete response and 14 patients (29%) showed a partial response. Overall response rate was 46% [95% confidence interval (CI) 33-60]. The median duration of response was 10.0 months. With a median follow-up of 18.0 months, the median time to progression was 11.9 months and the median overall survival was 27.1 months. The most frequently reported grade 3/4 hematological toxicity was neutropenia (19% of patients, 4% of cycles). Febrile neutropenia was reported in six patients (13%) and 7 cycles (2%), but no toxic deaths were reported. The most common grade 3/4 non-hematological toxicity was asthenia (17% of patients, 6% of cycles) and nail toxicity (15% of patients, 3% of cycles). In conclusion, biweekly docetaxel plus vinorelbine with G-CSF support is active and well tolerated as chemotherapy for patients with MBC resistant to anthracyclines. G-CSF support is recommended for lowering the incidence and severity of neutropenia and febrile neutropenia.     

Biweekly oxaliplatin plus irinotecan and folinic acid-modulated 5-fluorouracil: a phase II study in pretreated patients with metastatic colorectal cancer

Oxaliplatin (OXA) and irinotecan (IRI) are active drugs for metastatic colorectal cancer, their toxicity profiles are not overlapping, and both drugs have shown at least additivity with folinic acid-modulated 5-fluorouracil (5FU). We carried out this phase II study to assess the activity and toxicity of a biweekly regimen including OXA plus IRI on day 1, and levo-folinic acid (LFA) plus 5FU on day 2 (OXIRIFAFU) in pretreated patients with metastatic colorectal cancer. Forty-one patients, all previously treated with adjuvant and/or palliative 5FU-based chemotherapy (16 of them already exposed to IRI, OXA or both), were enrolled into this trial. On the basis of sensitivity to previous treatment, 19 patients were considered as chemo-resistant and 14 patients as chemo-refractory. OXA 110 mg/m (over 2 h) and IRI 175 mg/m (over 1 h) were delivered on day 1, followed by LFA 250 mg/m (2-h infusion) plus 5FU 800 mg/m as intravenous bolus on day 2. Cycles were repeated every 2 weeks. A total of 348 cycles were delivered, with a median of nine cycles per patient (range, 1-12 cycles per patient). Five complete and 13 partial responses were reported on 40 assessable patients, giving a response rate of 45% [95% confidence interval (CI), 29-62%]; eight of 19 (42%) resistant patients and five of 14 (36%) refractory patients achieved a major response, which was also obtained in four of eight (50%) patients pretreated with IRI and in three of eight (38%) patients pretreated with OXA. Grade 3 or higher neutropenia occurred in 68% of patients, but febrile neutropenia or infections affected only seven (17%) patients. No episodes of grade 3 or higher thrombocytopenia or anemia were recorded. Occurrence of severe non-hematologic toxicities by patients were: diarrhea, 34%; vomiting, 17%; peripheral cumulative neuropathy, 15%; stomatitis, 10%; acute cholinergic syndrome, 7%. Actually delivered dose intensities of all three drugs resulted in about two-thirds of the planned ones. After a follow-up of 39 months, median progression-free survival was 7.5 months. Median overall survival was 14.4 (95% CI, 10.4-18.4) months from the start of OXIRIFAFU and 25.3 (95% CI, 18.1-32.5) months from the diagnosis of metastatic disease. This OXIRIFAFU triplet regimen was highly effective in resistant/refractory colorectal cancer patients. A slight dose reduction of all cytotoxic drugs could be advisable in order to improve the tolerability of this regimen without jeopardizing its activity.     

Phase I study of the combination of oxaliplatin, irinotecan and continuous infusion 5-fluorouracil in digestive tumors

Oxaliplatin (L-OHP), irinotecan (CPT-11) and 5-fluorouracil (5-FU) have shown their efficacy in metastatic colorectal cancer. The synergism of these drugs has been demonstrated in vivo and in vitro. The aim of this study was to determine the recommended dose of the triple combination of L-OHP, CPT-11 and CI 5-FU for a further phase II study. Eighteen patients received the study treatment in four dose levels. The male:female ratio was 15:3 and the median age was 51.6 years (range 30-71). The type of tumor was colon in eight patients, rectum in four and other locations in six patients. The treatment was repeated every 2 weeks, at the fixed dose of L-OHP, 85 mg/m, and escalated doses of CPT-11 and 48-h infusion 5-FU of 100/2000, 100/2250, 125/2250 and 150/2250 mg/m. Only one previous treatment for the advanced disease was permitted. Patients received a median of 8 cycles (range 1-26) and a total of 152 cycles were administered. Dose intensity administered at dose level L-OHP 85 mg/m, CPT-11 150 mg/m and 5-FU 2250 mg/m was 95, 92 and 95% for L-OHP, CPT-11 and 5-FU, respectively. One patient in level 2 and one patient in level 4 presented dose-limiting toxicity that was not confirmed in the three required additional patients by level. The anti-tumor activity was assessed in nine patients: seven partial responses, one stable disease and one progressive disease. The maximum-tolerated dose was not reached, and thus the recommended dose for this combination schedule is L-OHP, 85 mg/m, CPT-11, 150 mg/m and 5-FU, 2250 mg/m 48-h continuous infusion, the same doses that were recommended for the drugs when administered in combination therapy of L-OHP + 5-FU or CPT-11 + 5-FU. A phase II study in first-line treatment of patients with metastatic colorectal cancer with this dose regimen is ongoing.     

Adding weekly irinotecan to high-dose 5-fluorouracil and folinic acid (HD-5-FU/FA) after failure for first-line HD-5-FU/FA in advanced colorectal cancer--a phase II study

Irinotecan (CPT-11) has been shown to prolong survival and improve quality of life in comparison to best supportive care in colorectal cancer patients with pretreatment of bolus 5-fluorouracil (5-FU). After first-line 24-h high-dose (HD) 5-FU/folinic acid (FA) an objective response rate of 11% with 3-weekly CPT-11 350 mg/m was reported. In the present study we investigated weekly CPT-11 in combination with 24-h HD-5-FU/FA as second-line treatment after prior exposure to 24-h HD-5-FU. Synergy between 5-FU and CPT-11 is the rationale to combine both substances for second-line therapy in order to overcome resistance to 5-FU. Thirty-five patients were recruited in a single institution to receive 6 x weekly CPT-11 80 mg/m(2), FA 200 mg/m(2) and 24-h HD-5-FU 2000 mg/m(2). Treatment was repeated on day 57. Patient characteristics: M/F=20/15, median WHO performance status 1, range (0-2). Thirty-four patients were evaluable for response: partial response 17% and no change 40%. Median time to progression and overall survival were 3.3 and 8.4 months, respectively. All patients were evaluable for toxicity analysis (National Cancer Institute Common Toxicity Criteria grade 3): leukocytopenia 3%, diarrhea 12% and vomiting/nausea 6%. Of the assigned doses, a median 100% of 5-FU and 92% of CPT-11 were administered during the first cycle of chemotherapy. We conclude that weekly CPT-11 and HD-5-FU/FA is an active and safe combination chemotherapy resulting in response rates in the upper range of other CPT-11-based second-line regimen. The toxicity profile in our series compared to 3-weekly CPT-11 seems favorable.     

Weekly high-dose 5-fluorouracil as 24-h infusion and folinic acid (AIO) plus irinotecan as second- and third-line treatment in patients with colorectal cancer pre-treated with AIO plus oxaliplatin

Our objective was to evaluate the efficacy and safety of high-dose 5-fluorouracil (5-FU) as a 24-h infusion and folinic acid (FA) (AIO regimen) plus irinotecan (CPT-11) after pre-treatment with AIO plus oxaliplatin (L-OHP) in colorectal carcinoma (CRC). Twenty-six patients with non-resectable distant CRC metastases were analyzed for second- or third-line treatment with AIO plus CPT-11 after pre-treatment with AIO plus L-OHP. On an outpatient basis, the patients received a treatment regimen comprising weekly 80 mg/m2 CPT-11 in the form of a 1-h i.v. infusion and 500 mg/m2 FA as a 1- to 2-h i.v. infusion, followed by 2000 mg/m2 5-FU i.v. administered as a 24-h infusion once weekly. A single treatment cycle comprised six weekly infusions followed by 2 weeks of rest. A total of 26 patients received 344 chemotherapy applications with AIO plus CPT-11. The main symptom of toxicity was diarrhea (NCI-CTC toxicity grade 3+4) occurring in five patients (19%; 95% CI 7-39%). Nausea and vomiting presented in two patients (8%; 95% CI 1-25%). The response rate of 26 patients can be summarized as follows: partial remission: n=7 (27%; 95% CI 12-48%); stable disease: n=9 (35%; 95% CI 17-56%) and progressive disease: n=10 (38%; 95% CI 20-59%). The median progression-free survival (n=26) was 5.8 months (range 3-13), the median survival time counted from the treatment start with the AIO plus CPT-11 regimen was 10 months (range 2-24) and counted from the start of first-line treatment (n=26) was 23 months (range 10-66). We conclude that the AIO regimen plus CPT-11 is practicable in an outpatient setting and well tolerated by the patients. Tumor control was achieved in 62% of the patients. The median survival time was 10 months and the median survival time from the start of first-line treatment (n=26) was 23 months.     

Clinical advances with topoisomerase I inhibitors in gastrointestinal malignancies

Phase III studies have shown irinotecan prolongs survival significantly when compared with either best supportive care or best infusional 5-fluorouracil (5-FU)-based chemotherapy in patients with 5-FU-resistant colorectal cancer. Phase I/II studies are investigating the combination of irinotecan with 5-FU, with thymidylate synthase inhibitors, notably raltitrexed, and with the oral fluoropyrimidines. Preliminary results suggest irinotecan and raltitrexed can safely be combined in the clinic and that this combination is active. The combination of irinotecan with the oral fluoropyrimidines also has produced promising results. A phase I study of irinotecan plus 5-FU/folinic acid showed high activity in first-line metastatic disease and further trials using the doses of 80 mg/m2 irinotecan plus 2 g 5-FU weekly are recommended. The combination of irinotecan with the De Gramont 5-FU regimen is feasible and active in patients with 5-FU-resistant metastatic disease. Alternating exposure to irinotecan and 5-FU may be as active as either treatment alone, and has been associated with overall response rates (ORRs) greater than 30% and encouraging median survival. The combination of irinotecan with oxaliplatin is also feasible and levels of response rates are in the region of 50% (especially with a 2-weekly administration schedule). In patients with advanced gastric cancer (including those with pretreated disease) ORRs of around 50% have been reported following administration of either cisplatin plus irinotecan or cisplatin plus docetaxel.     

草酸铂联合亚叶酸钙和5-氟脲嘧啶治疗晚期胃癌临床观察

目的 探讨草酸铂(L-OHP)联合亚叶酸钙(CF) 5-氟脲嘧啶(5-FU)方案治疗晚期胃癌近期疗效及其不良反应.方法 L-OHP 130mg/m2,静脉滴注3h,第d1;CF 100mg/m2,静脉滴注,第d1～5;5-FU150mg/m2,用CF之后静脉推注,同时5-FU 345mg/m2,静脉滴注,6～8 h,第d1-5,21d重复.结果 48例晚期胃癌患者,获CR 5例(10.4%),PR 24例(50%),SD 11例(22.9%),PD 8例(16.7%),总有效率(CR PR)达60.4%,主要不良反应为恶心、呕吐、白细胞和血小板降低及轻度周围神经毒性.结论 L-OHP联合CF 5-FU方案一线治疗晚期胃癌具有较好的疗效和安全性.     

Phase I, pharmacokinetic, and bone marrow drug-level studies of tri-monthly 48-h infusion of high-dose 5-fluorouracil and leucovorin in patients with metastatic colorectal cancers

The primary aim of the high-dose 5-fluorouracil (5-FU) and leucovorin (LV; HDFL48) phase I study was to determine the maximum tolerated dose and dose-limiting toxicity of 5-FU and LV with modified tri-monthly 48-h continuous infusion of high-dose 5-FU/LV in patients with metastatic colorectal cancer. The study also determined the pharmacokinetic parameters of 5-FU, especially steady-state plasma and bone marrow (BM) concentrations. Eligibility included serum triglyceride of more than or equal to 70 mg/dl, adequate BM function, and the major typical trial criteria. Sixteen patients who were enrolled received tri-monthly 5-FU at 2500 mg/m2/48 h/week (with 500 then 250 mg/m2/48 h/week escalation by a conventional 3-3 schema up to 3750 mg/m2/48 h/week) and LV at 300 mg/m2/48 h on days 1, 8, and 15 during a regular 28-day cycle. The maximum tolerated dose of 5-FU was 3750 mg/m2/48 h/week with this tri-monthly schedule. Dose-limiting toxicities were grade III neutropenia with more than 1-week delay of the next cycle, grade III mucositis, diarrhea, and hand-foot syndrome for more than 3 days. The regimen maintains significant concentration differences between steady-state plasma and BM concentrations (8.06 ± 6.39 vs. 2.89 ± 1.01 μmol/l, P=0.021) as measured by high-performance liquid chromatography. Toxicities were of minor grade and were tolerable, with minimal myelotoxicity significantly associated with low steady-state BM concentration. None had 5-FU-related hyperammonemic encephalopathy. Three patients had an objective partial response (18.8%, 95% confidence interval: 4-46%) and two of the 14 patients, who had failed HDFL24 (2600 mg/m2/24 h/week), had a partial response to HDFL48 (14.3% partial response, 95% confidence interval 2-43%). Median progression-free survival and overall survival were 4.1 months (range: 1.8-12.5) and 10.5 months (range: 2.7-32.1), respectively. The efficacy and low myelotoxicity of HDFL48 were attributed to the sustained adequate steady-state plasma concentration and an average 2.63-fold concentration gradient between plasma and BM compartments at steady state. The recommended 5-FU dose for use in future trials was 3500 mg/m2/48 h/week, with a fixed dose of LV at 300 mg/m2/48 h/week.     

Multifractionated paclitaxel and cisplatin combined with 5-fluorouracil and leucovorin in patients with metastatic or recurrent esophageal squamous cell carcinoma

This study assessed the clinical activity and safety of twice-weekly paclitaxel and cisplatin combined with 5-fluorouracil and leucovorin (TP-HDFL) in patients with recurrent or metastatic esophageal squamous cell carcinoma. The regimen, composed of paclitaxel 35 mg/m 1-h intravenous infusion on days 1, 4, 8 and 11; cisplatin 20 mg/m 2-h intravenous infusion on days 2, 5, 9 and 12; and 5-flourouracil 2000 mg/m and leucovorin 300 mg/m 24-h intravenous infusion on days 5 and 12; repeated every 21 days. Forty-one patients (median age 51), 15 with de-novo metastatic disease and 26 with recurrent disease, were enrolled. Grades 3-4 neutropenia, leukopenia and diarrhea occurred in 37.8, 29.4 and 14.2% of cycles, respectively. One patient died of invasive fungal infection. Three complete responses, 13 partial response and 13 stable diseases were observed. The intent-to-treat response rate was 39.0% (95% confidence interval: 24-54). The median progression-free and overall survival were 6.3 and 8.9 months (range 1-50+), respectively. Twice-weekly TP-HDFL has the activity and toxicity profile similar to the previously reported same three-drug combination for advanced esophageal cancer.